Innate immune cell recruitment in the fetus and neonate

doi:10.1016/j.jri.2011.01.022

Journal of Reproductive Immunology

Volume 90, Issue 1, June 2011, Pages 74-81

https://doi.org/10.1016/j.jri.2011.01.022 Get rights and content

Abstract

Recruitment of innate immune cells from the vasculature into infected tissue is a key event in primary host defense against invading pathogens. This highly regulated process requires a functional interplay of specialized adhesion molecules and involves a series of steps leading from rolling of leukocytes along the endothelium to firm adhesion and finally transmigration. In the developing fetus, innate immune functions are ontogenetically regulated and show increasing maturation throughout gestation. Developmental differences in the innate immune response leave the neonate and especially the premature newborn at high risk of severe infections. Understanding the ontogeny of immune functions in the fetus and newborn is therefore essential for the prevention and treatment of neonatal infections. In this review, an overview will be given of the developmental aspects of innate immune cell recruitment including a discussion of controversial findings and open questions.

Introduction

During intrauterine development, the fetal immune system is adapted to the special requirements of pregnancy (Szekeres-Bartho, 2002). This intricately regulated system is challenged when an infant is born prematurely leaving the newborn at high risk of infection, which is still a leading cause of neonatal morbidity and mortality (Lawn et al., 2010). The incidence of neonatal sepsis correlates inversely with gestational age and reaches levels as high as 58% in very low birth weight infants (Stoll et al., 2010). This inverse relationship reflects physiological changes in the fetal immune system during gestation. As the intrauterine environment is usually sterile, there is no obvious need for an adult-like immune response in the growing fetus. However, towards the end of gestation a functioning protection against the pending threats of extra-uterine pathogens becomes increasingly important. At birth, the neonatal adaptive immune system is still relatively naïve with respect to foreign antigens and the neonate relies to a large extent on the innate immune system for control and prevention of infection (Wynn et al., 2008, Levy, 2007). Understanding the development of innate immune functions is therefore essential for our understanding of the pathophysiology of neonatal infections. In this review, the authors aim to summarize current concepts of the fetal and neonatal innate immune response focusing on the essential steps and elements of innate immune cell recruitment. Where applicable, reference is made to ontogenetic differences in relation to gestational age. Although a functional interplay between the innate and the adaptive immune system already exists in neonates, aspects of the neonatal adaptive immune system will not be covered as this would reach beyond the scope of this article.

Section snippets

Immune cell recruitment

One of the central mechanisms in the cellular immune response against invading pathogens is the recruitment of leukocytes from the vasculature into infected or inflamed tissue. The recruitment process follows a well-defined cascade of events orchestrated by a complex interplay of adhesion molecules, cell surface receptors and chemokines as depicted in Fig. 1 (Ley et al., 2007). The initial capture of circulating leukocytes and the subsequent rolling of the cells along the endothelium are

Developmental aspects of selectin-dependent rolling

Rolling interactions between neutrophils (and other leukocyte subsets) and the endothelium require selectin–selectin ligand interactions. Of the three known selectins, P-selectin (CD62P) and E-selectin (CD62E) are upregulated on inflamed endothelial cells, while L-selectin (CD62L) is constitutively expressed on leukocytes and shed after cell activation (Sperandio, 2006). The major selectin ligand on leukocytes is P-selectin glycoprotein ligand-1 (PSGL-1, CD162), binding to all members of the

Developmental aspects of integrin-dependent adhesion

The transition from rolling to firm adhesion requires activation and binding of leukocyte-expressed integrins to endothelial adhesion molecules (Zarbock and Ley, 2008). On neutrophils, the major integrins involved in this process are the β₂ integrins LFA-1 (αLβ2, CD11a/CD18) and Mac-1 (αMβ2, CD11b/CD18), whereas monocytes also adhere through the β1 integrin VLA-4 (α4β1, CD49d/CD29). The respective counter-receptors expressed on inflamed endothelial cells with demonstrated in vivo relevance

Developmental aspects of transendothelial migration and chemotaxis

Once a leukocyte has adhered to the vessel wall, inside-out signals transduced by integrin-binding to its ligand lead to spreading and crawling of the cell along the endothelial lining before it transmigrates into the surrounding tissue (Ley et al., 2007). In order to reach the site of microbial invasion, extravasated leukocytes follow gradients of chemoattractants, which are either directly derived from the pathogen (e.g., fMLP) or produced by the host itself (chemokines, leukotrienes, etc.).

Impact of extrinsic factors on neonatal leukocyte recruitment

Besides developmental factors governing leukocyte recruitment in the fetus and newborn, many extrinsic factors have an influence on the recruitment process. In industrialized countries, virtually all infants born before 32 complete weeks’ gestation are exposed to antenatal steroids for induction of lung maturation. Steroids are known to reduce the endothelial expression of adhesion molecules, which is important for cell rolling and adhesion, including E-selectin, ICAM-1, and VCAM-1 (Aziz and

Concluding considerations and future prospects

Although many aspects of the neonatal innate immune response have been shown to be reduced compared with adults, it would be incorrect to state that the innate immune function in neonates is generally defective. The differences observed between neonates and adults rather reflect physiological alterations in the course of development. This is best seen when looking at the neonatal inflammatory response. It was initially believed that the inflammatory response in the developing fetus and neonate

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Innate immune cell recruitment in the fetus and neonate

Abstract

Introduction

Section snippets

Immune cell recruitment

Developmental aspects of selectin-dependent rolling

Developmental aspects of integrin-dependent adhesion

Developmental aspects of transendothelial migration and chemotaxis

Impact of extrinsic factors on neonatal leukocyte recruitment

Concluding considerations and future prospects

Blood

Blood

Cell Immunol.

Clin. Immunol.

Clin. Immunol. Immunopathol.

J. Pediatr.

Curr. Opin. Immunol.

Blood

Cytokine

Blood

J. Pediatr.

Blood

Semin. Perinatol.

Blood

Blood

Blood

Blood

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr.

Curr. Biol.

Blood

Am. J. Pathol.

E-selectin supports neutrophil rolling in vitro under conditions of flow

J. Clin. Invest.

Diminished lectin-, epidermal growth factor-, complement binding domain-cell adhesion molecule-1 on neonatal neutrophils underlies their impaired CD18-independent adhesion to endothelial cells in vitro

J. Immunol.

Decreased adherence, chemotaxis and phagocytic activities of neutrophils from preterm neonates

Acta Paediatr. Scand.

Soluble L-selectin (sCD62L) umbilical cord plasma levels increase with gestational age

Pediatr. Res.

Neutrophil chemotaxis and adhesion in preterm babies

Arch. Dis. Child

The ontogeny of adhesion molecules expressed on the vascular endothelium of the developing human skin

J. Anat.

Expression of cell adhesion molecules in the fetal gut

Adv. Exp. Med. Biol.

The effect of betamethasone on neonatal neutrophil chemotaxis

Pediatr. Res.

Increased respiratory burst and increased expression of complement receptor-3 (CD11b/CD18) and of IL-8 receptor-A in neutrophil granulocytes from newborns after vaginal delivery

Biol. Neonate